The Nrf2 activator, tBHQ, inhibits IL-2 production by human T cells in a largely Nrf2-independent manner

Abstract

Abstract Nrf2 is a transcription factor that is activated by cell stress, such as oxidative insult and exposure to xenobiotics. Upon activation, Nrf2 translocates to the nucleus, where it upregulates its target genes, many of which arecytoprotective in function. Nrf2 has been shown to modulate immune function; Nrf2-null mice are more sensitive to many models of inflammatory disease, including experimental autoimmune encephalitis and sepsis induced by cecal ligation and puncture. We have previously shown that activation of Nrf2 in primary mouse CD4 T cells promotes Th2 differentiation, which may have implications on the development of allergy and asthma. However, the role of Nrf2 in human CD4 T cell function remains uncharacterized. Thus, the purpose of the present studies was to determine the role of Nrf2 in the early events following CD4 T cell activation. Primary human CD4 T cells from peripheral blood were treated with varying concentrations of tBHQ (a known Nrf2 activator) prior to activation with anti-CD3/anti-CD28. Although treatment of human T cells with tBHQ suppressed the production of early cytokines, such as IL-2, the model fell short in determining whether these effects were Nrf2-dependent. Toward that end, Nrf2-null T cells were generated by implementation of CRISPR-CAS9 gene editing, in human Jurkat T cells. Treatment of Nrf2-null and Wild-type Jurkat T cells demonstrated that the effects of tBHQ upon cytokine production are largely independent of Nrf2. In contrast, suppression of CD25 expression by tBHQ is partially Nrf2-dependent. The current studies demonstrate that many of the effects of tBHQ on early events following CD4 T cell activation are independent of Nrf2. (This work was funded by NIH grants ES018885 and GM092715)